Topiramate, a substituted fructo-pyranose derivative, is a promising agent for the treatment of cocaine dependence, presumably because by reducing its rewarding affects associated with abuse liability. We propose two experiments using state-of-the-art human abuse liability assessment techniques to examine the subjective, behavioral, and physiological effects of cocaine both alone and in combination with topiramate. All studies will be double-blind and placebo-controlled using balanced (for sequence and position) cross-over designs in male and female non treatment-seeking cocaine abusers (total N = 42). The first experiment, a proof-of-concept systematic extension of our own preliminary study, will test the hypothesis that sub-acute topiramate significantly reduces acute cocaine-mediated changes in subjective mood and other abuse liability assessments. As a secondary objective of this experiment, we will characterize the cocaine's effects on cognition and physiological response in non-fatigued subjects during drug-taking, and determine if, and by how much, these effects are altered by topiramate. This placebo-controlled, double-blind, 3 x 3 counterbalanced, Latin Square, cross-over study will examine the effects of low- and high-dose combinations of both cocaine (0.325 mg/kg and 0.650 mg/kg i.v. I and topiramate (100 mg and 200 mg orally) in 18 non-treatment-seeking, cocaine-dependent men and women. The second experiment will test the hypothesis that the most effective topiramate dose from experiment #1, when administered chronically, also will reduce acute cocaine-mediated subjective mood. We also will characterize the effects of chronic topiramate treatment on acute cocaine-induced cognitive and physiological changes. This placebo-controlled, double-blind study will use 24 non-treatment-seeking, cocaine-dependent male and female subjects in a nested 2 x 3 factorial, counterbalanced, cross-over design to examine the pharmacological interaction between the optimal topiramate dose and low- and high-dose cocaine. In summary, experiment # I provides a proof-of-concept analysis of topiramate's ability to reduce cocaine's abuse potential. Experiment # 2 more directly addresses issues of potential clinical effectiveness and tolerability with which to guide efficacy trials. The results of these human laboratory studies should provide a solid basis for planning clinical trials examining the safety and effectiveness of topiramate for the treatment of cocaine-dependent individuals.